The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam. bantam-mediated repression of the E3 ligase–associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.

在许多情况下，Ras 信号传导的激活是肿瘤发生的主要早期事件，但自相矛盾的是，Ras 信号传导诱导细胞衰老，从而防止肿瘤发生。因此，Ras 激活的细胞必须克服衰老才能发展为癌症。通过黑腹果蝇的基因筛选，我们发现 ETS 家族转录激活因子 Pointed (Pnt) 是必要且足以在 Ras 激活时触发细胞衰老并阻止 Ras 诱导的眼触角盘中肿瘤生长。通过使用各种遗传工具分析镶嵌盘，我们确定了一种肿瘤进展机制，其中细胞极性的丧失是上皮肿瘤发生的常见驱动因素，通过 microRNA 介导的 Pnt 抑制消除了 Ras 诱导的细胞衰老。从机制上讲，Ras 激活细胞中的极性缺陷导致 Hippo 效应器 Yorkie (Yki) 的激活，从而诱导了 microRNA bantam的表达。矮脚鸡介导的 E3 连接酶相关蛋白 Tribbles (Trbl) 的抑制减轻了对转录因子 FoxO 的 Ras 和 Akt 依赖性抑制。Ras 激活细胞中 FoxO 活性的恢复诱导了 microRNA miR-9c和miR-79的表达，从而导致pnt表达降低，从而消除细胞衰老并促进肿瘤进展。我们的研究结果为 Ras 激活的肿瘤如何通过克服细胞衰老向恶性肿瘤发展提供了机制解释。